Mariam Arabi

Homozygous familial hypercholesterolemia in Lebanon: A genotype/phenotype correlation

Familial hypercholesterolemia (FH) is an inherited disease characterized by the deposition of LDL in tissues causing premature atherosclerosis. Many genes are implicated in FH resulting in a large variability in the phenotype. DNA sequencing of the LDLR gene was done for forty patients clinically diagnosed with homozygous FH and forty family members variably affected. Patients underwent noninvasive heart and vascular studies. Statistical and pedigree analyses were used to correlate the different genotypes with the phenotypes. The prevalence of homozygosity at the Lebanese allele (2043C>A) is 45%. However, 27.5% of the patients have no mutations at all in the LDLR gene, and 27.5% are either heterozygous for the 2043C>A mutation, heterozygous for a mutation in another exon of the LDLR gene, or combined heterozygous for two different mutations. We confirm previous reports on the higher prevalence of FH in Lebanon. Our results do, however contradict previous reports on an assumed higher prevalence among the Christian Lebanese. Mutations in the LDLR especially combined heterozygosity can cause a severe phenotype similar to the homozygous mutation in the Lebanese allele. This information is particularly important in targeting the more prevalent heterozygotes in the general population with early diagnosis and intervention.

Primary carnitine deficiency: novel mutations and insights into the cardiac phenotype

Solute carrier family 22 member 5 (SLC22A5) encodes a sodium‐dependent ion transporter responsible for shuffling carnitine across the plasma membrane. This process provides energy for the heart, among other organs allowing beta‐oxidation of fatty acids. Mutations in SLC22A5 result in primary carnitine deficiency (PCD), a disorder that manifests with cardiac, skeletal, or metabolic symptoms. We hereby describe two novel mutations in SLC22A5 in two Lebanese families associated exclusively with a cardiac phenotype. The frequency of the cardiac, metabolic and skeletal symptoms in PCD patients remains undefined. All the reported eight PCD patients belonging to five different Lebanese families have an exclusive cardiac phenotype. Carnitine levels appear to be directly linked to the type and position of the mutation and the severity of the phenotypic presentation does not seem to be associated with serum carnitine levels. A comprehensive review of 61 literature‐reported PCD cases revealed an exclusive cardiac manifestation frequency at 62.3% with a very low likelihood of simultaneous occurrence of cardiac and metabolic manifestation.

Pulmonary hypertension in children and young adults with sickle cell disease: evidence for familial clustering.

Pulmonary hypertension (PHTN) is increasingly recognized as a serious complication of sickle cell disease (SCD). Our objective was to determine the prevalence of PHTN and identify factors associated with PHTN among children and young adults with SCD in Lebanon.

NKX2-5 Mutations in an Inbred Consanguineous Population: Genetic and Phenotypic Diversity

NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population.

Primary carnitine deficiency: Novel mutations and insights into the cardiac phenotype

Solute carrier family 22 member 5 (SLC22A5) encodes a sodium‐dependent ion transporter responsible for shuffling carnitine across the plasma membrane. This process provides energy for the heart, among other organs allowing beta‐oxidation of fatty acids. Mutations in SLC22A5 result in primary carnitine deficiency (PCD), a disorder that manifests with cardiac, skeletal, or metabolic symptoms. We hereby describe two novel mutations in SLC22A5 in two Lebanese families associated exclusively with a cardiac phenotype. The frequency of the cardiac, metabolic and skeletal symptoms in PCD patients remains undefined. All the reported eight PCD patients belonging to five different Lebanese families have an exclusive cardiac phenotype. Carnitine levels appear to be directly linked to the type and position of the mutation and the severity of the phenotypic presentation does not seem to be associated with serum carnitine levels. A comprehensive review of 61 literature‐reported PCD cases revealed an exclusive cardiac manifestation frequency at 62.3% with a very low likelihood of simultaneous occurrence of cardiac and metabolic manifestation.

Cardiac tamponade as the first manifestation of systemic lupus erythematosus in children

Systemic lupus erythematosus (SLE) is a serious chronic autoimmune disease with intense inflammatory response and damage in many target organs including joints, skin, kidneys, heart and nervous system. Cardiac tamponade is extremely rare as a cardinal presentation of SLE in children with only a few cases reported in the literature. We report two cases of a 9-year-old boy and an 11-year-old girl presenting with acute cardiac tamponade and later recognition of elevated anti-double-stranded DNA (anti-dsDNA) titre. We also present a literature review about similar cases in children and we stress on the importance of screening all cases of acute cardiac tamponade in children with antinuclear and anti-dsDNA antibodies to avoid any delay in SLE diagnosis and treatment.

Percutaneous closure of patent ductus arteriosus in children using amplatzer duct occluder II: Relationship between PDA type and risk of device protrusion into the descending aorta

To compare the efficacy and safety of Amplatzer Duct Occluder II (ADOII) among the various patent ductus arteriosus (PDA) types, and to assess the association between development of aortic obstruction and the PDA type in terms of measurable parameters as the device angulation and distance of upper end protrusion into the aortic lumen.

Low-Density Lipoprotein Levels and Not Mutation Status Predict Intima-Media Thickness in Familial Hypercholesterolemia

BACKGROUND Intima-media thickness (IMT) is a well-described marker of cardiovascular disease. In this study we aim to determine whether low-density lipoprotein (LDL) levels and disease-related mutation status can predict IMT in patients with severe familial hypercholesterolemia (FH) referred for or on LDL apheresis. METHODS Genetic screening, lipid profile testing, and IMT measurements were performed on a series of 33 severe FH patients (19 homozygous) on LDL apheresis treatments (LDL 447 ± 151 mg/dL, age range 6-60 years). Data were then compared with literature IMT-LDL data for normal subjects, mild FH patients, and severe FH patients (18, 41, and 6 studies, respectively). RESULTS Age-adjusted IMT was linearly related to LDL levels over a wide range of values (<500 mg/dL), except for the severe FH no-apheresis cohort. Alternatively, our severe FH population (mostly on apheresis) did follow the mild FH/control age-adjusted IMT-LDL relation. CONCLUSIONS In severe FH, measuring LDL levels is more predictive of increased IMT than genetic screening.

A Novel Mutation in FOXC1 in a Lebanese Family with Congenital Heart Disease and Anterior Segment Dysgenesis: Potential Roles for NFATC1 and DPT in the Phenotypic Variations

Congenital heart diseases (CHDs) are still the leading cause of death in neonates. Anterior segment dysgenesis is a broad clinical phenotype that affects the normal development of the eye, leading in most of the cases to glaucoma which is still a major cause of blindness for children and adolescents. Despite tremendous insights gained from genetic studies, a clear genotype–phenotype correlation is still difficult to draw. In Lebanon, a small country with still a high rate of consanguineous marriages, there are little data on the epidemiology of glaucoma amongst children with or without CHD. We carried out whole exome sequencing (WES) on a family with anterior segment dysgenesis, and CHD composed of three affected children with glaucoma, two of them with structural cardiac defects and three healthy siblings. The results unravel a novel mutation in FOXC1 (p. R127H) segregating with the phenotype and inherited from the mother, who did not develop glaucoma. We propose a digenic model for glaucoma in this family by combining the FOXC1 variant with a missense variant inherited from the father in the dermatopontin (DPT) gene. We also unravel a novel NFATC1 missense mutation predicted to be deleterious and present only in the patient with a severe ocular and cardiac phenotype. This is the first report on FOXC1 using WES to genetically characterize a family with both ocular and cardiac malformations. Our results support the usage of such technology to have a better genotype–phenotype picture for Mendelian-inherited diseases for which expressivity and penetrance are still not answered.

The Muscle-Bound Heart

Hypertrophic cardiomyopathy (HCM) is a familial cardiac disease manifested in a wide phenotype and diverse genotype and, thus, presenting unpredictable risks mainly on young adults. Extensive studies are being conducted to categorize patients and link phenotype with genotype for a better management and control of the disease with all its complications. Because the full mechanisms behind HCM are still not revealed, therapeutics are not definitive. Further research is to be conducted for the generation of a complete picture and directed therapy for HCM.